EP0639069B1 - Forme galenique pour administration oculaire et procede de preparation - Google Patents

Forme galenique pour administration oculaire et procede de preparation Download PDF

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Publication number
EP0639069B1
EP0639069B1 EP93910086A EP93910086A EP0639069B1 EP 0639069 B1 EP0639069 B1 EP 0639069B1 EP 93910086 A EP93910086 A EP 93910086A EP 93910086 A EP93910086 A EP 93910086A EP 0639069 B1 EP0639069 B1 EP 0639069B1
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EP
European Patent Office
Prior art keywords
tablet
tablet according
glycerides
polymer
active principle
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP93910086A
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German (de)
English (en)
French (fr)
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EP0639069A1 (fr
Inventor
Jean-Marc Aiache
Gilbert Serpin
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Individual
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Individual
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to dosage forms intended for the ocular administration of active principles which it is desired to deliver in a more or less prolonged manner, as well as a process allowing their preparation.
  • tear fluid results in rapid elimination of all conventional drug forms applied to the surface of the eye.
  • 20% of the instilled drop can be retained by the eye, five minutes after administration only 8% of the 20% remain in the conjunctival cul-de-sac. This is due to the renewal of the lacrimal fluid which can be increased due to the irritation caused by gout. From this short contact time, or even protein binding, it follows that there is only a small fraction that enters the eye.
  • Conventional means such as increasing the viscosity of eye drops, adding surfactants, oily solutions or ointments are not very effective.
  • the new technologies developed in recent years seek to bring other advantages such as a regular concentration of active ingredients in the tear fluid, for a more sustained pharmacological response, a reduction in side effects and a less demanding dosage, which should improve patient compliance.
  • insoluble extra-ocular implants of the Ocusert® type appeared in 1973 in the United States. They are in the form of two crimped, insoluble, semi-permeable membranes containing the solution of active medicinal ingredients which in a few days slowly release at the level of the conjunctival dead ends.
  • this type of product leads to many tolerance problems, which limit their use.
  • Extra-ocular implants were then developed. They are the subject of a Pro-Pharmacopea monograph in April- May 1988 (No. 500) under the name of ophthalmic insert.
  • Hitoschi Ozawa Biomaterials, vol. 4, July 1983 studied the interest of ocular inserts impregnated with antibiotics (including erythromycin) in the treatment of trachoma in rabbits and their behavior in vitro.
  • antibiotics including erythromycin
  • FR-2 140 114 describes compositions comprising one or more lipophilic substances having a melting point of 37 to 75 ° C. and a higher surfactant alcohol, these compositions being able to be shaped in the form of a unit administration dose, which will soften on body temperature.
  • insoluble solid form which can be easily removed from the eye after releasing the active ingredients, would be preferable.
  • the polymer or polymers constituting the matrix form a network which traps the molecules of active principle and gradually release them.
  • Part of the glycerides forming the first coating layer may be present within the matrix. They act as a lubricant during compression. Their quantity is modulated so that they are distributed on the surface of the core and form a regular and homogeneous layer, of variable thickness according to the speed of release of the active principle which is sought.
  • the central core of the dosage form may also contain the excipients necessary for its formulation and known to those skilled in the art, such as wetting, binder, suitable diluent.
  • the polymer (s) used for the matrix is chosen in particular from the group comprising polyethylene, acrylic polymer, polyvinyl chloride, cellulose derivatives of the HPMC type, polyvinyl alcohol, Eudragit®.
  • Eudragits are a family of acrylic resin type compounds marketed by Röhm Pharma GmbH.
  • solid glycerides glycerides which are either in powder or in liquid form adsorbed on supports.
  • Natural or semi-synthetic glycerides are preferably used, in particular triglycerides. Mention may be made, for example, of Compritol®, or glycerol behenate.
  • the dosage form also comprises a second layer, forming an external semi-permeable membrane.
  • This external membrane has a double function. On the one hand, by playing the role of dialyzing barrier, it allows better control of the rate of release of the active ingredient (s) present in the matrix structure of the nucleus.
  • this coating improves the tolerance of the dosage form in vivo and therefore allows prolonged maintenance without the side effects of irritation observed with conventional inserts.
  • the second layer is formed from a thermo-plastic derivative of cellulose, for example ethylcellulose or cellulose acetate. It is up to the person skilled in the art to choose any other compound capable of ensuring the functions of a semi-permeable membrane.
  • the dosage form according to the invention is a tablet that can be placed in the conjunctival cul-de-sac of the patient, in order to gradually release the active ingredients there.
  • its dimensions are included, for the length between approximately 2.5 and 4 mm and for the diameter between approximately 1 and 3 mm.
  • Such tablets have optimal properties with regard to the qualitative composition, size and strength of the tablets. These forms can be easily placed and removed from the conjunctival cul-de-sac without leaving debris.
  • the dosage forms according to the invention contain at least one active principle chosen from the group comprising mydriatics, antibiotics and anti-inflammatories.
  • tablets of elongated shape are prepared, containing, in the central matrix, two mydriatics, acting according to a different mechanism, neosynephrine and tropicamide.
  • Neosynephrine used in the form of its hydrochloride, is an alpha-adrenergic stimulant used as a decongestant and mydriatic vasoconstrictor.
  • Tropicamide is a parasympatholytic of the antimuscarinic family, which blocks acetylcholine receptors, mainly those of the iris sphincter and the ciliary muscles; it is used clinically in the treatment of uveitis in order to obtain cycloplegia, in particular for intervention on the lens.
  • Such tablets after sterilization with gamma rays, can be placed for 1 to 2 hours in the conjunctival cul-de-sac of preoperative patients and then removed just before the surgical operation of the conditioned eye.
  • the active principle is present at a rate of between 1 and 60%
  • the polymer of the matrix is present at a rate of between 25 and 70%
  • the glycerides are present at a rate of 8 to 40%, based on the total weight of the tablet.
  • the mixture of the active ingredient (s) with the polymers and any adjuvants must be sufficiently homogeneous for the glycerides to be distributed inside and outside the tablet during compression; for this purpose, an optional granulation will be carried out, before the addition of the glycerides.
  • the method according to the invention is characterized in that after step (d), a step of coating the tablet is carried out with a thermoplastic derivative in solution in an organic solvent.
  • This additional step makes it possible to form the second dialyzing layer or membrane.
  • the coating can in particular be carried out in a turbine or in a fluidized air bed.
  • Ethylcellulose is for example used in hydro-alcoholic solution and drying is done under a fluidized air bed.
  • these tablets are then sterilized, preferably by gamma radiation.
  • FIG. 1 represents the curve of the percentages released of active principle, cumulative, for the tablets of formula 5, as a function of time.
  • Neosynephrine is in the form of small crystals. These tablets being for ophthalmic use, it is necessary to have very fine powders. Neosynephrine hydrochloride is therefore ground beforehand, unlike tropicamide, the powder of which is sufficiently fine. The active ingredients are then sieved through a 0.400 mm mesh sieve as well as the excipients of the internal and external phase.
  • the active ingredients and the excipients are then weighed and mixed in the Turbula for ten minutes.
  • the powder mixture is wetted with Kenwood followed by granulation on a 1 mm grid.
  • the grains obtained are dried in a ventilated oven for 4 hours at 45 ° C. before being calibrated on a 0.630 mm grid, for the formulas: 1.2.3 and 0.315 mm for the formulas: 4.5.5 ' for reasons explained later.
  • the grains are then weighed and mixed with the external phase.
  • the last step consists of direct compression on an alternative machine.
  • the punches used are the same as for formula 4 and the grain is calibrated on a 0.315 mm mesh grid.
  • the tablets are soaked one by one using a small colander, five successive times, between each soaking they are dried placed on non-woven paper in an oven at 50 ° C.
  • the tablet is placed in a hermetically closed plastic tube of 20 ml capacity and filled with 20 ml of 0.9% NaCl solution.
  • the tube is then fixed to the stirring system of the in vitro dissolution device for the Rotating Bottles (described in the National Formulary XV) and stirred at a constant speed of 20 revolutions / minute).
  • the whole is placed in an oven at 37 ° C.
  • One tenth of the liquid (ie 2 ml) is then withdrawn at determined times and renewed with the same quantity of new solvent (0.9% NaCl).
  • the sampling times are: 2,6,10,15,20,25,30,35,40,45,60 minutes.
  • the samples are then analyzed by HPLC
  • the percentages released in vitro accumulated are described by a curve with time on the abscissa and the percentages released on the ordinate.
  • the objective is to determine in an rabbit objectively the possible irritant properties and the mydriatic effect (the moment of onset of mydriasis and its evolution over time) caused by the tablets during their single administration in the eye. rabbit which consists of placing one of these forms in the conjunctival cul-de-sac of the rabbit.
  • New Zealand Albino rabbit from a specialized breeding whose weight is between 1.5 kg and 2.5 kg.
  • the animals are individually identified by ear tattooing.
  • the animals are housed in cages with standardized dimensions.
  • the cages are placed in an air-conditioned pet store (17-21 ° C) maintained at a hygrometric degree between 45 and 65% relative humidity except during cleaning hours in which the filtered non-recycled air is renewed.
  • the nycthemeral cycle is artificially recreated under the following conditions: 12 hours of light / 12 hours of darkness.
  • Degree of clouding - No visible change or loss of shine in the sun O-0 - Presence of translucent areas (diffuse or scattered), details of the iris clearly visible O-1 - Presence of an easily identifiable translucent area, details of the iris slightly masked O-2 - Presence of an opalescent, no detail of the visible iris, barely discernible outline of the pupil O-3 - Presence of total corneal opacity making the iris and the pupil invisible O-4
  • the kinetics of the mydriatic effect is even slower: the maximum mydriasis is obtained shortly before 30 minutes.
  • the tolerance is excellent after administration of the coated tablets of formula 5 'for which the rabbits do not seem to be affected in any way by the treatment.
  • the coating would play the role of matrix which would slow the release of neosynephrine and tropicamide.
  • the tablets of batch 1 cause numerous irritations, in particular severe tearing.
  • the vessels of the palpebral conjunctiva are slightly more injected than normal and the eyelids are slightly swollen. After the withdrawal of the tablets these signs disappear, they seem mainly due to the presence of these tablets in the conjunctival cul-de-sac.
  • the tablets of the other formulas only have slight tearing in general. Rabbits that have had the coated tablets show no signs of irritation. This good tolerance is due to the small size of the tablets, their hardness and their smoother appearance. In addition, the active ingredients seem to be released much more gradually than for the other tablets of the previous formulas.
  • the tests are carried out under medical supervision by a clinician following an established protocol.
  • Each patient is assigned the number 1, 2, 3 or 4.
  • the edges of the tablets are sharp, which partly explains the hemorrhagic petechiae.
  • the size of the tablets is considered ideal. After 30 minutes, the tablet is very soft, it remains whole during the ablation which is carried out almost spontaneously by simply pressing on the edge of the lower eyelid. The doses of the mydriatic product seem good.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
EP93910086A 1992-05-05 1993-05-05 Forme galenique pour administration oculaire et procede de preparation Expired - Lifetime EP0639069B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9205514 1992-05-05
FR9205514A FR2690846B1 (fr) 1992-05-05 1992-05-05 Forme galenique pour administration oculaire et procede de preparation.
PCT/FR1993/000433 WO1993021901A1 (fr) 1992-05-05 1993-05-05 Forme galenique pour administration oculaire et procede de preparation

Publications (2)

Publication Number Publication Date
EP0639069A1 EP0639069A1 (fr) 1995-02-22
EP0639069B1 true EP0639069B1 (fr) 1997-10-29

Family

ID=9429535

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93910086A Expired - Lifetime EP0639069B1 (fr) 1992-05-05 1993-05-05 Forme galenique pour administration oculaire et procede de preparation

Country Status (8)

Country Link
US (1) US5766619A (ja)
EP (1) EP0639069B1 (ja)
JP (1) JP3208568B2 (ja)
KR (1) KR100206481B1 (ja)
DE (1) DE69314950T2 (ja)
ES (1) ES2109493T3 (ja)
FR (1) FR2690846B1 (ja)
WO (1) WO1993021901A1 (ja)

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19511322C2 (de) * 1995-03-28 1999-09-02 Mann Gerhard Chem Pharm Fab Sterile Augengele mit einem Gehalt an mittelkettigen Triglyceriden und Verfahren zu deren Herstellung
WO2000040089A1 (en) * 1999-01-05 2000-07-13 Massachusetts Eye And Ear Infirmary Targeted transscleral controlled release drug delivery to the retina and choroid
US6416777B1 (en) * 1999-10-21 2002-07-09 Alcon Universal Ltd. Ophthalmic drug delivery device
ATE290837T1 (de) 1999-10-21 2005-04-15 Alcon Inc Medikamentenversorgung der sub-tenon
BR0014929B1 (pt) 1999-10-21 2009-01-13 dispositivo para distribuiÇço de medicamento oftÁlmico.
US7943162B2 (en) * 1999-10-21 2011-05-17 Alcon, Inc. Drug delivery device
WO2002089767A1 (en) 2001-05-03 2002-11-14 Massachusetts Eye And Ear Infirmary Implantable drug delivery device and use thereof
EP1409065B1 (en) 2001-07-23 2007-01-17 Alcon, Inc. Ophthalmic drug delivery device
ES2271301T3 (es) * 2001-07-23 2007-04-16 Alcon, Inc. Dispositivo de suministro de farmaco oftalmico.
WO2003092665A2 (en) * 2002-05-02 2003-11-13 Massachusetts Eye And Ear Infirmary Ocular drug delivery systems and use thereof
US20060167435A1 (en) * 2003-02-18 2006-07-27 Adamis Anthony P Transscleral drug delivery device and related methods
JP2007505932A (ja) * 2003-09-18 2007-03-15 マクサイト， インコーポレイテッド 経強膜送達
US8663639B2 (en) * 2005-02-09 2014-03-04 Santen Pharmaceutical Co., Ltd. Formulations for treating ocular diseases and conditions
CA2597590A1 (en) * 2005-02-09 2006-08-17 Macusight, Inc. Formulations for ocular treatment
JP2009502954A (ja) 2005-07-27 2009-01-29 ユニバーシティ オブ フロリダ リサーチ ファウンデーション，インコーポレイティド タンパク質のミスフォールディングを修正する小分子及びその使用
WO2007013590A1 (ja) * 2005-07-29 2007-02-01 Santen Pharmaceutical Co., Ltd. 固形組成物を用いた後眼部組織への非侵襲性ドラッグデリバリーシステム
UA94427C2 (ru) 2005-11-29 2011-05-10 Смиткляйн Бичам Корпорейшн Фармацевтическая композиция для местного лечения неоваскулярных расстройств глаз
US8492400B2 (en) 2006-02-09 2013-07-23 Santen Pharmaceutical Co., Ltd. Stable formulations, and methods of their preparation and use
CN103127100A (zh) 2006-03-23 2013-06-05 参天制药株式会社 用于与血管通透性有关的疾病或病症的制剂和方法
US20080265343A1 (en) * 2007-04-26 2008-10-30 International Business Machines Corporation Field effect transistor with inverted t shaped gate electrode and methods for fabrication thereof
US8372036B2 (en) 2009-05-06 2013-02-12 Alcon Research, Ltd. Multi-layer heat assembly for a drug delivery device
IN2012DN00352A (ja) 2009-06-16 2015-08-21 Bikam Pharmaceuticals Inc
US20120232102A1 (en) 2009-09-30 2012-09-13 Chun-Fang Xu Methods Of Administration And Treatment
US8177747B2 (en) 2009-12-22 2012-05-15 Alcon Research, Ltd. Method and apparatus for drug delivery
WO2012174064A1 (en) 2011-06-14 2012-12-20 Bikam Pharmaceuticals, Inc. Opsin-binding ligands, compositions and methods of use
WO2013058809A1 (en) 2011-10-19 2013-04-25 Bikam Pharmaceuticals, Inc. Opsin-binding ligands, compositions and methods of use
JP6126118B2 (ja) 2011-11-30 2017-05-10 ビカム ファーマスーティカルス，インコーポレイテッド オプシン結合性リガンド、組成物、及び使用方法
AU2012346537A1 (en) 2011-12-01 2014-07-17 Bikam Pharmaceuticals, Inc. Opsin-binding ligands, compositions and methods of use
CN109549922B (zh) * 2018-12-27 2021-04-20 湖北远大天天明制药有限公司 一种托吡卡胺眼用组合物及其制备方法与应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3630200A (en) * 1969-06-09 1971-12-28 Alza Corp Ocular insert
SE352811B (ja) * 1971-06-04 1973-01-15 Pharmacia Ab
US3986510A (en) * 1971-09-09 1976-10-19 Alza Corporation Bioerodible ocular device
US3828777A (en) * 1971-11-08 1974-08-13 Alza Corp Microporous ocular device

Also Published As

Publication number Publication date
WO1993021901A1 (fr) 1993-11-11
JPH07506356A (ja) 1995-07-13
DE69314950T2 (de) 1998-04-16
US5766619A (en) 1998-06-16
FR2690846A1 (fr) 1993-11-12
EP0639069A1 (fr) 1995-02-22
FR2690846B1 (fr) 1995-07-07
ES2109493T3 (es) 1998-01-16
DE69314950D1 (de) 1997-12-04
KR950701214A (ko) 1995-03-23
KR100206481B1 (en) 1999-07-01
JP3208568B2 (ja) 2001-09-17

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